间充质干细胞在胶质瘤治疗中的作用研究

Mesenchymal stem cells as therapeutic agents and in gene delivery for the treatment of glioma 间充质干细胞在胶质瘤治疗中的作用研究 first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:cxiang@zju.edu.cn †E-mail:cxiang@zju.edu.cn cxiang@zju.edu.cn State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Mesenchymal stem cells (MSCs) are plastic-adherent cells with a characteristic surface phenotype and properties of self-renewal, differentiation, and high proliferative potential. The characteristics of MSCs and their tumor-tropic capability make them an ideal tool for use in cell-based therapies for cancer, including glioma. These cells can function either through a bystander effect or as a delivery system for genes and drugs. MSCs have been demonstrated to inhibit the growth of glioma and to improve survival following transplantation into the brain. We briefly review the current data regarding the use of MSCs in the treatment of glioma and discuss the potential strategies for development of a more specific and effective therapy. 胶质瘤是颅内发病率最高的恶性肿瘤，虽然临床上可以用"手术+化疗"的方法进行治疗，但由于其浸润性，对化疗药物的低敏感性等原因，常在治疗后复发，严重威胁人类生命健康。间充质干细胞（MSC）是干细胞中的一员，具有增殖能力强、分化潜能大、免疫原性低及采集方便等优点，其趋化性更使MSC成为肿瘤治疗的一个理想工具。本文对干细胞治疗胶质瘤的研究现状进行了归纳总结，着重阐述了MSC的旁分泌途径作用及作为基因载体导入肿瘤坏死因子相关凋亡诱导配体（TRAIL）、溶瘤病毒等其他治疗基因的生物功能，以期对进一步的治疗研究提供帮助。 Cancer Glioma Mesenchymal stem cells Stem cells Therapy 癌症 间充质干细胞 胶质瘤 细胞治疗 Introduction 1 Malignant glioma, the most prevalent primary malignant brain tumor, is one of the most aggressive and lethal human cancers. Despite surgical resection and chemotherapy, glioma always recurs, resulting in poor patient prognosis (Surawicz et al., 1998 1998 ; Deangelis, 2001 2001 ). Tumor cells that infiltrate the surrounding crucial areas of the brain and cannot be eliminated successfully are thought to be responsible for tumor regrowth (Keles and Berger, 2004 2004 ; Lefranc et al., 2005 2005 ). New therapies that target single tumor cells residing in normal brain tissue are in serious demand. Mesenchymal stem cells (MSCs), also called mesenchymal stromal cells, have been the focus of research aimed at developing a new clinical therapy for glioma for years. It was difficult to predict how MSCs would change the focus of research when they were first identified by McCulloch and Parker ( 1957 1957 ). Subsequent studies were performed to delineate the properties of MSCs. Friedenstein et al. ( 1970 1970 ) found that fibroblasts from bone marrow are capable of spontaneous bone formation and are able to induce osteogenesis in diffusion chambers. In 1974, the capacities of self-renewal and multipotential differentiation of human bone marrow-derived MSCs (BM-MSCs) were demonstrated (Friedenstein et al., 1974 1974 ). In the 1980s, the plasticity of these cells was also revealed (Owen and Friedenstein, 1988 1988 ). Over several decades, MSCs were identified in many tissues, including adipose tissue, umbilical cord blood, and dental pulp, and they were used in the development of treatments of many types of diseases (Zuk et al., 2001 2001 ; Parolini et al., 2008 2008 ; Nagano et al., 2010 2010 ). In 2000, an annual meeting of the International Society for Cellular Therapy (ISCT) reported on the “stemness” of these cells and recommended clarification of the nomenclature for progenitor cells (Dominici et al., 2006 2006 ). The above mentioned characteristics make MSCs a potentially valuable therapeutic tool. This article reviews the recent findings of MSC on the therapy of glioma to provide a better understanding of the current situation. Migration: tumor-tropic 1 Currently, gene therapy, in which an antitumor substance is delivered to a tumor, has been applied for treatment but has shown only limited success in clinical trials (Castro et al., 2003 2003 ). The main reason for this limited success may be the inefficient and unsustained spread of vectors in tumors (Pulkkanen and Yla-Herttuala, 2005 2005 ). The discovery of the tumor-tropic capability of MSCs highlights the potential for overcoming these shortcomings. The tropism of MSCs to glioma was first demonstrated by Nakamura et al. ( 2004 2004 ). This group implanted human umbilical cord-derived MSCs (UC-MSCs) in the contralateral hemisphere, distant from established gliomas. After implantation, migration of MSCs along the corpus callosum was observed. Further, tumor-tropic migration was shown to be increased in immunocompromised mice injected with human BM-MSCs into the ipsilateral and contralateral carotid arteries (Nakamizo et al., 2005 2005 ), whereas implanted rat fibroblasts remained at the injection site and did not migrate to the rat 9L glioma (Miletic et al., 2007 2007 ). Near-infrared (NIR) fluorescence imaging confirmed the tumor tropism and distribution of UC-MSCs (Kim et al., 2016 2016 ). Pre-exposure of human adipose tissue-derived MSCs (AT-MSCs) to conditioned media of U87 glioma cells and extracellular matrix proteins could enhance their homing to brain cancer (Smith et al., 2015 2015 ). However, Bexell et al. ( 2012 2012 ) found no evidence of long-distance rat BM-MSCs migration through the intact striatum toward syngeneic D74 (RG2), N32, and N29 gliomas in the ipsilateral hemisphere or across the corpus callosum to gliomas located in the contralateral hemisphere, while MSCs of intratumoral origin migrated extensively, specifically within N32 gliomas. In addition, Bexell et al. ( 2009 2009 ) found that intratumoral implantation resulted in a more efficient distribution of rat BM-MSCs than intravenous (i.v.) injection. This decreased efficiency observed with i.v. injection may have been due to the trapping of i.v. injected MSCs in the lungs of the mice, resulting in their inability to reach the arterial system (Harting et al., 2009 2009 ; Prockop, 2009 2009 ). These findings indicate that the route of MSC delivery and the source of MSCs may be important factors for the extent of MSC engraftment. Above all, the tumor-tropic capacity of MSCs makes them potential vectors for the delivery of antitumor substances to gliomas without causing adverse effects on normal brain tissue. Many previous studies have demonstrated MSC migration; however, the precise underlying mechanism remains unknown. An early report published by Hidemitsu Sato et al. ( 2005 2005 ) revealed that murine BM-MSCs transduced with epidermal growth factor receptor (EGFR) had stronger migratory abilities than non-transduced MSCs and that the enhanced migration of EGFR-MSCs may be attributed to EGF-EGFR, protein kinase C, mitogen-activated protein (MAP) kinase, and actin polymerization. In addition, Nakamizo et al. ( 2005 2005 ) have found that growth factors, such as platelet-derived growth factors, stromal-derived factor-1, and epidermal growth factor, but not basic fibroblast growth factor, may play important roles in human BM-MSC migration. Subsequently, other studies have shown that chemokines, such as monocyte chemoattractant protein-1 (MCP-1), growth-related oncogene (GRO)-α, interleukin (IL)-8, and IL-12, enhance the tumor-tropic ability of MSCs (Kim et al., 2009 2009 ; 2011 2011 ; Xu et al., 2010 2010 ; Ryu et al., 2011 2011 ). This migration may occur through CXC chemokine receptor 1 (CXCR1), CXCR2, and CXCR4. Further, antagonist or antibody treatment against chemokines could reduce these migration events. In addition to chemokines, other factors may influence the tumor-tropic ability of MSCs. Fewer observed p27 −/− MSCs in the C6 tumor area compared with p27 +/+ MSCs implied the function of p27 in the migration of murine BM-MSCs (Gao et al., 2010 2010 ). Matrix metalloproteinases (MMPs), which are zinc-dependent endopeptidases, participate in the migratory activities of various MSCs. Knock-out of MMP1 causes inhibition of the migratory abilities of MSCs. Conversely, its overexpression in poorly migrating MSCs enhances their migratory abilities. In addition, disruption of the interaction between MMP1 and protease-activated receptor 1 (PAR1) seriously inhibits the migratory abilities of human BM-MSCs (Ho et al., 2009 2009 ). An in vivo study has demonstrated that rat BM-MSC migration and vessel formation are decreased in the presence of inhibitors of angiogenic signaling factors (Bexell et al., 2009 2009 ). Another study suggests that UC-MSCs migration is dependent, at least in part, on angiogenic signaling factors and that it may share common pathways with tumor angiogenesis (Kim et al., 2009 2009 ). This could be a potential advantage of the use of MSCs for the treatment of glioma. Due to the different MSC sources and isolation protocols, it is difficult to compare studies for determining the precise mechanisms of MSC migration. Though the studies above have revealed some possible ways, further research is needed to elucidate the precise molecular mechanisms before these cells can be used in the treatment of glioma. Therapeutic effects of MSCs 1 MSC migration has been demonstrated in many studies, but the exact function of these cells in the tumor microenvironment remains unknown. In lymphoma-bearing mice, intraperitoneal injection of human BM-MSCs has been demonstrated to improve survival through induction of endothelial cell (EC) apoptosis (Secchiero et al., 2010 2010 ). Further, Otsu et al. ( 2009 2009 ) have found that endothelial derived-MSCs (EC-MSCs) cause capillary degeneration in a co-culture system of MSCs and ECs and that they intercalate into the capillary networks of ECs to inhibit B16F10 melanoma growth in vivo. In addition, an antitumor function of human UC-MSCs exerted through upregulation of PTEN in glioma cells (SNB19, U251, 4910, and 5310) has been subsequently demonstrated (Dasari et al., 2010 2010 ). Considering the preceding reports, Ho et al. ( 2013 2013 ) explored the biological effects of human BM-MSCs using a tumor model of immunodeficient BALB/c-u/nu mice. In this study, the researchers inoculated primary human glioma cells and carboxymethyl-DiI-labeled MSCs from human bone marrow into the mice. After 21 d, the mice were sacrificed. A peripheral rim of tumor cells bordering a zone of necrosis was observed in hematoxylin and eosin (H & E)-stained co-cultured tumor sections, but necrosis was not observed in the DGli36 or DGli36/iNHA tumor section. Subsequently, the researchers evaluated vessel morphology and microvessel density by CD31 staining and pericyte coverage (α-smooth muscle actin (α-SMA)) analyses. The results showed that CD31 cells were present in regional areas of the representative DGli36 and DGli36/MSC tumor sections and that α-SMA cells were only present in the DGli36/MSC sections. Next, the researchers found that the presence of BM-MSCs inhibited tube formation by 50% in the DGli36 co-culture by in vitro angiogenesis assay, indicating that BM-MSCs may impair tumor angiogenesis through the release of anti-angiogenic factors. A proteome array performed using harvested conditional medium (CM) and quantitative polymerase chain reaction (Q-PCR) of the co-cultured cells revealed that platelet-derived growth factor (PDGF)-BB, phosphorylated Akt, and cathepsin expression was decreased. The researchers concluded that the PDGF/PDGFR (PDGF receptor) axis, which plays a key role in glioma angiogenesis, may also have an important role in the antitumor effects of MSCs. In another study, the researchers found that cord UC-MSCs inhibited U87 glioblastoma multiforme growth and promoted apoptosis (Akimoto et al., 2013 2013 ). This inhibition may be mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and downregulation of cyclin D1 expression (Jiao et al., 2011 2011 ; Akimoto et al., 2013 2013 ). In addition, conditioned media from human AT-MSCs and UC-MSCs have been shown to efficiently induce apoptosis and differentiation of human U251 glioma cell lines in vitro (Yang et al., 2014 2014 ). Kolosa et al. ( 2015 2015 ) found that the expression of cyclin D1 was downregulated when NCH421k cells were cultured in the MSC-CM. However, they thought that the cycle arrest was rather associated with the senescence and differentiation of the glioma cells than with apoptosis, though the mitochondrial membrane potential was decreased. Using PCR array and flow cytometry, Kolosa et al. ( 2015 2015 ) revealed significantly deregulated expression of 13 genes associated with senescence including ATM , CDKN1A , and CDKN2A and expression of the differentiation markers such as neuronal marker b III tubulin, vimentin, and glial fibrillary acidic protein (GFAP). These also increased the sensitivity of the glioma cell toward temozolomide. This was consistent with the study of Motaln et al. ( 2012 2012 ) that human BM-MSCs may promote the senescence of the tumor cells by inducing cell morphology and cytokine changes. In contrast, other studies have reported that MSCs also promote tumor growth. Djouad et al. ( 2003 2003 ) have shown that murine C3H10T1/2 MSCs favor B16 tumor growth in allogeneic animals by exerting an immunosuppressive effect. Further, Karnoub et al. ( 2007 2007 ) have reported that BM-MSCs promote tumor growth in breast cancer metastasis (MCF7/Ras, MDA-MB-231, MDA-MB-435, and HMLER), and Coffelt et al. ( 2009 2009 ) have reported similar promotion of growth of OVCAR-3 tumors. Additionally, Pillat et al. ( 2016 2016 ) suggested that BM-MSCs may promote U87 glioma invasion both in co-cultures indirectly or directly, by increasing the expression of kinin B1 receptor (B1R), kinin B2 receptor (B2R), and matrix metalloproteases in U87. In addition, several studies have reported that MSCs have no apparent effect on N32 tumor cell growth (Komarova et al., 2006 2006 ; Kucerova et al., 2007 2007 ; Bexell et al., 2009 2009 ). Another study using extracellular vesicles from different sources has revealed that the different effects of BM-, UC-, and AT-MSCs on U87 tumor cell growth may depend on the tissue of origin (del Fattore et al., 2015 2015 ). This finding demonstrates the complexity of MSCs. Further study is necessary before MSCs can be used in clinical therapy. MSC delivery of therapeutic genes 1 Because of the complex effects of MSCs on tumors and their unsatisfactory results in the treatment of glioma, research on MSCs has focused more on pioneering their use in gene transfer. The gene most commonly used is TRAIL . TRAIL , a member of the tumor necrosis factor (TNF) superfamily, was first identified and cloned by its sequence homology to TNF and CD95L (Wiley et al., 1995 1995 ). It efficiently induces apoptosis of cancer cells. Additionally, it is not toxic to normal cells (Wu, 2009 2009 ). These factors make TRAIL an attractive genetic tool for use in the treatment of tumors. Choi et al. ( 2011 2011 ) were the first to demonstrate short-and long-term therapeutic efficacies using TRAIL-producing human AT-MSCs. Their study included both in vitro and in vivo experiments. In the in vitro experiment, the researchers co-cultured TRAIL-producing AT-MSCs and F98 glioma cells in a Transwell tissue culture plate. After 3 d, the number of F98 cells cultured with TRAIL-producing AT-MSCs was decreased by 59.5% compared with that of the control F98 cells cultured alone. In the in vivo experiment, the researchers intratumorally implanted MSCs into rats at 3 d after inoculation of F98 tumor cells. The animals were sacrificed and fixed after 18 d. Histological analysis revealed that the tumor volume was reduced by 56.3% in the TRAIL-producing AT-MSCs-treated rats compared with the phosphate buffered saline (PBS)-treated and AT-MSCs-treated rats. In a survival experiment with a maximum duration of 100 d, the TRAIL-producing AT-MSC group also exhibited significantly increased survival. These results demonstrate the therapeutic efficacy of MSCs expressing TRAIL. Other studies have reported that BM-MSCs are very tolerant of the transfection of TRAIL-bearing vectors (Tang et al., 2014 2014 ) and that MSC-based secretable trimeric TRAIL ( stTRAIL ) gene delivery exhibits greater therapeutic efficacy than direct injection of adenovirus encoding the stTRAIL gene into a C6 tumor mass. TRAIL also can be combined with other genes, such as thrombospondin-1, in therapy to achieve enhanced effects (Choi et al., 2015 2015 ). Transfection of both stTRAIL and three type-1 repeats (3TSR) domain of thrombospondin-1 into AT-MSC could up-regulate DR4/DR5 expression and induce apoptosis of the HBMVEC glioma cells via caspase 3/7/8. Simultaneously, AT-MSCs-3TSR inhibits angiogenesis and sensitizes brain ECs to TRAIL in a CD36-dependent manner. The combination displayed a synergistic cytotoxic effect. Collectively, these studies have demonstrated the benefits and potential of TRAIL in stem cell-based targeted gene therapy for clinical application. However, despite the effectiveness of TRAIL in many tumors, some types of tumor cells, including glioma cells, are resistant to TRAIL -induced apoptosis, suggesting that the use of TRAIL alone may not be sufficient. Thus, novel drugs are required that sensitize glioma cells to TRAIL -induced apoptosis, or new strategies are needed to overcome TRAIL resistance that can be combined with MSCs- TRAIL . Working toward these goals, different groups have explored various methods, including the use of TRAIL along with chemotherapeutic agents (Johnson et al., 2013 2013 ; Kim et al., 2014 2014 ), radiotherapy (Kim et al., 2010 2010 ), lipoxygenase (Kim et al., 2012 2012 ), and carbenoxolone (Yulyana et al., 2013 2013 ). These methods have all had better therapeutic results than those using TRAIL alone. Combined treatment with TRAIL and another agent may be a novel and useful strategy for improving treatment of malignant glioma. Other cytokines have also been engineered into MSCs for the treatment of glioma. Inhibition of tumor growth by cytokine transfer using MSCs has been demonstrated in many tumor models. These cytokines include IL-2, IL-12, IL-18, interferon (IFN)-α, IFN-β, CXC3CL1, EGFR, and vascular endothelial growth factor A (VEGF-A) (Studeny et al., 2002 2002 ; Nakamura et al., 2004 2004 ; Sato et al., 2005 2005 ; Schichor et al., 2006 2006 ; Hong et al., 2009 2009 ; Xu et al., 2009 2009 ; Park et al., 2015 2015 ). CD4 + and CD8 + T cells, infiltration by natural killer cells, and long-term antitumor immunity probably enhanced these results. Peripheral immunotherapy using IFN-γ-transduced autologous tumor cells with intratumoral delivery of IL-7 was also demonstrated in regressed rat gliomas and was shown to improve the survival of glioma-bearing rats (Gunnarsson et al., 2010 2010 ). Further analysis revealed that this improvement was mediated through the secretion of low levels of the immunosuppressive molecules IL-10 and prostaglandin E2 and enhancement of the responses of major histocompatibility complex (MHC) classes I and II to IFN-γ treatment (Strojby et al., 2014 2014 ). The prodrug-converting enzyme cytosine deaminase (CD) is a suicide gene that converts the prodrug 5-fluorocytosine (5-FC) to a toxic metabolite 5-fluorouracil (5-FU). 5-FU, an inhibitor of RNA synthesis, can cross the blood-brain barrier easily and is nontoxic to normal neuronal cells. It makes 5-FU an effective drug for the treatment of brain tumors. Gene therapy with 5-FC/CD also induces a strong bystander effect that does not require direct cell-to-cell contact (Ichikawa et al., 2000 2000 ). However, due to the inefficient, unsustained spread of vectors in tumors, there is a need for a more efficient and specific vector system, such as MSCs, to achieve substantial therapeutic effects. A regimen involving transduction of CD into human BM-MSCs and subsequent injection of the MSCs intracranially has been demonstrated to have anti-cancer effects in early-stage brain tumors and to repress C6 tumor cell growth during the later stage (Chang et al., 2010 2010 ). Accordingly, this therapeutic regimen has been reported to be efficacious in some cancers, such as glioma (Lee et al., 2009 2009 ; Kosaka et al., 2012 2012 ; Song et al., 2012 2012 ), colon carcinoma (Kucerova et al., 2007 2007 ), prostate tumor (Cavarretta et al., 2010 2010 ), and melanoma (Kucerova et al., 2008 2008 ). Further, genetically engineered MSCs have been shown to exhibit therapeutic efficacy against brainstem glioma. Carboxylesterase enzyme (CE) efficiently converts the prodrug CPT-11 (irinotecan-7-ethyl-10-(4-(1-piperidino)-1-piperidino)carbonyloxycamptothecin) into the active drug SN-38 (7-ethyl-10-hydroxycamptothecin), a potent topoisomerase I inhibitor. As activation of CPT-11 by human esterase is poor, exogenous CE would be very useful for converting CPT-11 to SN-38 (Wierdl et al., 2001 2001 ; Danks et al., 2007 2007 ). Choi et al. ( 2012 2012 ) have demonstrated that human AT-MSCs engineered with CE exhibit more effective growth inhibition of F98 cells and significantly increased survival than MSCs alone MSC delivery of viruses 1 Oncolytic virus preferentially infects and kills cancer cells by lysis. As the infected cancer cells are destroyed, they release new infectious virus particles to help destroy the remaining tumor (Ferguson et al., 2012 2012 ). The results of the Phase I and Phase II clinical trials in glioblastoma multiforme (GBM) patients had showed the anti-tumor activity and safety of oncolytic adenoviruses (Parker et al., 2009 2009 ). However, oncolytic viruses are often neutralized by immune reactions following injection due to the high immunogenicities of the viral particles (Lichty et al., 2014 2014 ). Thus, cellular vectors that protect oncolytic viruses from host immune systems are very much needed. Using human BM-MSCs as delivery vectors, oncolytic viruses have been applied in the treatment of mice bearing human U87 gliomas and ovarian tumors (Komarova et al., 2006 2006 ; Yong et al., 2009 2009 ). Further, human AT-MSCs with a hyaluronidase-expressing oncolytic virus have been demonstrated to have even better effects in the treatment of glioma (U87-MG, LN308, U138, and LN229) (Martinez-Quintanilla et al., 2015 2015 ). The herpes simplex virus-thymidine kinase ( HSV-tk ) gene is another commonly used prodrug-converting enzyme with a strong bystander anti-cancer effect. It converts the prodrug ganciclovir into its toxic form and inhibits DNA synthesis, resulting in cell death. Engineering of the HSV-tk gene into BM-MSCs results in its more efficient distribution within tumors compared with injection of this gene with viral vectors. Recently, HSV-tk -engineered MSCs in combination with systemic administration of ganciclovir have been used in the treatment of C6 glioma (Amano et al., 2009 2009 ; Uchibori et al., 2009 2009 ; Chang et al., 2010 2010 ) and Panc02 pancreatic cancer (Zischek et al., 2009 2009 ). When coupled with the HSV-tk -ganciclovir prodrug cancer gene therapy system, with delivery by either implantation into the opposite hemisphere or injection into xenografts, EC-MSCs have been demonstrated to inhibit U87 and HTB14 tumor growth and to prolong the survival of mice (Kinoshita et al., 2010 2010 ; Bak et al., 2011 2011 ; de Melo et al., 2015 2015 ). Additionally, Matuskova et al. ( 2010 2010 ) have demonstrated the formation of gap junctions between AT-MSCs and human glioblastoma cells (8-MG-BA, 42-MG-BA, and U-118). The gap junctions rendered the tumor cells refractory to TK-MSC-mediated cytotoxicity. This result supports the mechanism of bystander cytotoxicity and the further use of MSCs in the treatment of glioma. MSC delivery of miRNA 1 MicroRNAs (miRNAs) are important tools used to target numerous mRNAs, and some miRNAs are potent tumor suppressors (Croce, 2009 2009 ). However, they cannot be injected directly because they are easily degraded. Fortunately, miRNAs are abundant in extracellular exosomes, which are 30–150 nm vesicles secreted by a wide range of mammalian cells that can be transferred between cells through their uptake and release (Hu et al., 2012 2012 ). Katakowski et al. ( 2013 2013 ) transfected BM-MSCs with a miR-140b expression plasmid and harvested exosomes released by the MSCs, obtaining exosomes containing functional miR-140b. Following intratumoral injection of the exosomes into a rat primary brain tumor model, they found that the growth of the glioma xenograft was inhibited. This finding suggests that the inclusion of specific therapeutic miRNAs into MSC exosomes may represent a new treatment strategy for malignant glioma. Prospects for clinical MSC-based glioma therapy 1 Malignant glioma is a primary malignant brain tumor that cannot yet be successfully eliminated. Because of their robust tropism for intracranial glioma, MSCs are highly attractive vehicles for the direct delivery of a wide variety of therapeutic gene products to tumor cells, and they can also be used to target tumor cells directly. In addition, MSCs can be easily harvested and amplified, which makes them a reliable tool for the treatment of tumors. Further, following implantation of MSCs transduced with an anti-tumor substance into tumors, the cells migrate and deliver the substance to tumors that are inaccessible by surgery, and they function synergistically. However, extensive research must be performed before MSC-based therapy can be used in the clinic. 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This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1600337 Project supported by the National High-Tech R&D Program (863) of China (No. 2015AA020306) 2016-07-25 2016-11-22 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany 2017 2017 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 09 18